tbuckley/cabot-search huggingface dataset:
Abstract 13122: Exome Sequencing Reveals Novel Genetic Variants Predisposing to Sudden Cardiac Death Due to Primary Myocardial Fibrosis
Authors: Juhani Junttila, Lasse Pakanen, Sini Skarp, Anne Doedens
Journal: Circulation (2022)

Introduction: Sudden cardiac death (SCD) is one of the most common modes of death in Western countries. In post-mortem investigations, myocardial fibrosis is a common finding, as more than 90% of the SCD victims have fibrotic accumulation in the myocardium. Hypothesis: Our aim was to identify novel candidate genes and variants predisposing to the development of myocardial fibrosis in SCD victims. Methods: Whole exome sequencing was performed for 127 nonischemic SCD cases with primary myocardial fibrosis as the only pathological finding. We searched for rare variants with minor allele frequency &lt;0.005 estimated to be pathogenic and present in three or more cases. A computational approach was used to identify protein interactions for candidate genes in cardiomyocytes. Associations of the identified variants with cardiovascular disease endpoints were investigated in the Finnish national genetic study (FinnGen) dataset. Results: We identified 21 missense and one nonsense variant in SCD victims with primary myocardial fibrosis. Most variants locate in genes participating in extracellular matrix (ECM) formation, inflammation, mitochondrial function, cardiomyocyte contractility or hypertrophy. Heart enhanced protein interactions were identified for 16 candidate genes. Ten variants were significantly associated with SCD and primary myocardial fibrosis (adjusted p-value &lt;0.05). Sixteen variants were also associated with cardiac diseases in Finnish general population. Four missense variants were highly likely to be pathogenic, significantly associated with sudden cardiac death due to primary myocardial fibrosis and were also associated with cardiac diseases in general Finnish population. These variants locate in cartilage acidic protein 1 ( CRATC1 ), the calpain 1 ( CAPN1 ), unc-45 myosin chaperone A (UNC45A) and unc-45 myosin chaperone B (UNC45B). Conclusions: We identified novel variants and candidate genes predisposing to sudden cardiac death due to primary myocardial fibrosis. Our results highlight the importance ECM pathways as well as cardiomyocyte function and survival in the pro-fibrotic process.
Abstract 13237: Single Cell Transcriptomes Reveal Novel Macrophage and Endothelial Subtypes in Pulmonary Hypertension
Authors: Bolun Li, Yanjiang Xing, Yitian Zhou, Xingqi Xiao, Ting Shu, Xiaomin Song, Hongmei Zhao, Junling Pang, Peiran Yang, Paul B Yu, Jing Wang, Chen Wang
Journal: Circulation (2022)

Introduction: Animal models are widely used to study pulmonary hypertension and test experimental therapies. The detailed cellular phenotypes of these diverse models, and their relationship to human disease remain unclear. Hypothesis: This study aimed to assess several commonly used models and their correlations with human disease at single-cell resolution. Methods: Single-cell RNA sequencing was performed on lung tissues from mice exposed to chronic hypoxia or SU5416 with hypoxia, rats exposed to monocrotaline, and control animals. Immunofluorescence was used to validate the findings in animal and patient tissues. Results: Perturbed cell populations in diseased rats and mice were similar to those in patients, with macrophages and endothelial cells being primarily affected. A novel DHCR24 high macrophage population harboring tissue remodeling and pro-inflammatory features were consistently increased across rodent models, and whose phenotypic modulation corresponded with disease progression. Functionally diverse endothelial subtypes were found, including a novel ETB + endothelial population with potentially protective functions. These endothelial subtypes exhibited key motifs of pulmonary hypertension, including enhanced apoptosis, dysregulated angiogenesis, proliferation, and reactive oxygen species-mediated stress. These macrophage and endothelial subtypes exhibited dysregulation of numerous genes targeted by approved PAH drugs. Changes in these cell populations were confirmed by animal and patient lung histology. Potential intercellular interactions between macrophage and endothelial subtypes, via ANGPTL4, CXCL12, or SEMA3 signaling, and autocrine endothelial signaling were predicted to occur. Conclusions: We established a comprehensive single-cell atlas of the mainstream rodent pulmonary hypertension models, and highlighted potential functional roles of novel macrophage and endothelial subpopulations.
Abstract 12781: Trends in Remote Monitoring for Patients With Hf and Identification of Opportunities to Expand Rural Access
Authors: Lauren Gilstrap, Christopher Leggett, James O'Malley, Heather Carlos, Sandra Wong, sally kraft, Matthew Mackwood, Jonathan Skinner
Journal: Circulation (2022)

Introduction: Limited access, due to geographic and/or transportation barriers, is one of the most significant challenges to chronic disease management in rural areas. Remote monitoring is a potential solution that allows a patients’ implanted devices to be interrogated for arrhythmia and non-invasive hemodynamics without the patient travelling to clinic. The aim of this study is to describe recent trends in remote monitoring among patients with HFrEF and to identify barriers and expand access in rural areas. Methods: We created annual, cross-sectional cohorts of patients with HF in each year from 2013 to 2018 with approximately 5 million patients/year by requiring ≥1 inpatient or ≥2 outpatient ICD9/10 codes for HF in the 2 years prior. Remote interrogation was determined using ICD-9/10 and CPT codes. Rurality was determined using the beneficiaries’ ZIP code of residence and the Rural/Urban Commuting Areas (RUCA) classification. The outcome of interest was the number of HFrEF patients with ≥1 remote monitoring visit in each year between 2013 and 2018. Results: The use of remote monitoring increased 21% between 2013 and 2018 in patients with HFrEF. By 2018, 9.3% of patients had ≥1 remote monitoring event (Figure 1). After multivariable adjustment for patient factors, living in a rural area was associated with a 14% greater odds (95% CI 1.13, 1.14, p&lt;0.001) of remote monitoring. However when hospital referral region (HRR), a geographic delineation of health care markets, was added to the model, living in an urban area became associated with a 7.8% greater odds of remote monitoring (95% CI 1.07, 1.08, p&lt;0.001). Conclusion: Remote monitoring is used by approximately 10% of patients with HFrEF. The most significant driver of remote monitoring is the HRR, or health care market, that the beneficiary resides in. To increase remote monitoring for rural patients, hospitals in predominately rural HRR’s should be incentivized to expand remote monitoring services.
Abstract 12756: Gender Differences in Physical and Depressive Symptoms of Heart Failure in a Propensity Matched Sample
Authors: Mary Roberts Davis, Shirin O Hiatt, Nathan Dieckmann, Lissi Hansen, Nandita C Gupta, Christopher S Lee, Quin E Denfeld
Journal: Circulation (2022)

Introduction: There are a number of gender differences in heart failure (HF) care and outcomes; yet there remain gaps in our understanding of gender differences in HF symptoms. The aim of this study was to use propensity matching to examine gender differences in physical and depressive HF symptoms between women and men. Methods: Data from 6 studies of unique patients with NYHA Functional Class I-IV HF were combined. Across all studies, physical symptoms were measured with the HF Somatic Perception Scale (HFSPS; including two subscales - Early &amp; Subtle and Dyspnea), and depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9). Using clinical and behavioral characteristics based on prior gender research in HF, a propensity score was derived for each participant. Then, nearest neighbor matching was performed to determine pairs of women and men with similar propensity scores and examined the average treatment effects (ATE) between genders on the symptom measures. Results: Nearest neighbor matching yielded 183 matched pairs (n = 366). The average age was 58 years. Common clinical characteristics were: non-ischemic etiology (66%), systolic HF (83%), hypertension (53%), Type II Diabetes (23%), and atrial fibrillation (43%). The average mean difference in symptom scores between women and men (ATE), is displayed in Table 1. Women reported lower scores on all symptom measures compared with men; however, this difference was not statistically significant. Conclusions: In this propensity matched sample of women and men with HF, there were no significant gender differences in physical and depressive symptom scores. Additional gender-balanced research is needed to elucidate nuances in symptom presentation among women with HF.
Abstract 14407: Clinical Outcomes of Transcatheter Aortic Valve Replacement in Patients With Bicuspid versus Tricuspid Aortic Valve Stenosis
Authors: Yasser Radwan, Enhua Wang, Mohammad F Salam, Khalid Saeed Al-Asad, Adnan Halboni, Abdullah Al-abcha, Yehia Saleh, george Abela
Journal: Circulation (2022)

Introduction: Transcatheter aortic valve replacement (TAVR) has proven to be safe and efficacious in patients with tricuspid aortic valve (TAV) stenosis. However, due to its anatomic complexity, bicuspid aortic valve (BAV) stenosis has been excluded from previous trials, and data remain limited regarding TAVR in this group of patients. Methods: We searched the databases systematically for relevant studies from inception to March 2022. The primary focus was all-cause mortality at 1-year. Additional outcomes included 30-day mortality, 30-day stroke, and 30-day major vascular complications. Results: We included 28 studies with a total of 346,033 patients who underwent TAVR, of which 17,835 patients had BAV stenosis. The risks of 1-year mortality and 30-day major vascular complications were similar between the 2 groups. However, patients with BAV who underwent TAVR had a higher risk of 30-days mortality (BAV 2.3% vs TAV 2.2%, p=0.02) and 30-day stroke (BAV 2.2% vs TAV 1.8%, p=0.01). A subgroup analysis of 23,623 matched patients of whom 49.5% had BAV stenosis was performed. The risk of 1-year mortality was lower in patients with BAV compared to TAV (BAV 5.8% vs TAV 6.8%, p=0.009). Risks of 30-day mortality, and 30-day major vascular complication were similar between the two groups. However, the risk of 30-day stroke was higher in the BAV group (BAV 2.2% vs TAV 1.7%, p=0.02). Conclusions: In our meta-analysis, among patients who underwent TAVR for aortic stenosis, there was no significant difference between BAV vs TAV in outcomes, except for higher risk of 30-days mortality and stroke. Among matched groups, patients with BAV stenosis undergoing TAVR had comparable outcomes to patients with TAV stenosis except for higher risk of stroke and lower risk of 1-year mortality in BAV group.More studies, specifically randomized trials, are still warranted to further assess efficacy, safety and reassure the long-term outcomes in this group of patients.
Abstract 13501: Gaps in Care With Pediatric Hypertension Diagnosis: Role of Social Determinants of Health
Authors: Abbas H Zaidi, Jonathan Miller, Kristin Maiden, Zhongcui Gao, Yendelela L Cuffee
Journal: Circulation (2022)

Background: Primary hypertension (HTN) in pediatrics is a significant public health concern with increasing prevalence. The risk for adult HTN and end-organ damage begins in childhood. Therefore, evidence-based guidelines were developed by the American Academy of Pediatrics (AAP) in 2017 with detailed recommendations on screening and diagnosis. Ongoing follow-up is essential for diagnosis (at least 3 follow-up visits are needed to diagnose HTN if BP is high). However, gaps in care(GIC) exist in detecting and diagnosing HTN in clinical practice with barriers to accurate HTN detection at the patient, provider, and health system levels. Patient factors such as social determinants of health (SDoH), including the Childhood Opportunity Index (COI), leading to GIC with recommended follow-up needed for HTN diagnosis at primary care visits are poorly understood. Methods: A total of 69,960 patients aged 6-22 years seen at Nemours Children’s Health in DE and PA between August 2017- March 2019 formed the cohort. SDoH, including language, race, ethnicity, and COI, were explored. Data were analyzed using descriptive statistics and logistic regression. Results: Only 596 patients(0.9%) had HTN or were recognized as having a high BP. 73%(432) patients had over a 1-year GIC. GIC was associated with insurance type(P=0.05) and having 2 or fewer caregivers(P=0.004). GIC was not associated with race, ethnicity, language, interpreter use, or COI. Conclusions: Despite evidence-based guidelines, HTN detection remains poor. Patient factors, including insurance and the number of caregivers, likely lead to GIC with follow-up for HTN in pediatric patients. However, GIC for routine HTN follow-up are not broadly associated with SDoH. Other barriers likely exist at the provider and health system level leading to GIC and poor HTN detection.
Abstract 13079: Reduced Apoj-Glyc Serum Levels Identify Patients With Cardiac Ischemic Events Among Those Attending the Emergency Department With Chest Pain
Authors: Juan-Carlos C Kaski, Judit Cubedo, Nuria Lluch, Jose L Lopez-sendon, Diana Gorog, Isabel Antorrena, Pablo Avanzas, Pablo Herrero Puente, Alessandro Sionis, Jose R Gonzalez-Juanatey, Andrés Iñiguez, Alberto Cordero, Emmanuel Ako, Francisco Fernandez-Aviles, Felipe Atienza, Alejandro Recio-Mayoral, Lina Badimon
Journal: Circulation (2022)

Introduction: Glycosylated apolipoprotein J (ApoJ-Glyc) has been suggested to be a marker for the early detection of myocardial ischemia. Ischemia induces an intracellular accumulation of non-glycosylated ApoJ that mirrors a reduction in ApoJ-Glyc serum concentration in acute ischemic syndromes. Objective: The EDICA clinical trial - multi-centre, international, diagnostic study (NCT04119882)- was carried out to assess the performance of ApoJ-Glyc as a biomarker for the early detection of myocardial ischemia in patients attending the A&amp;E department with chest pain suggestive of acute coronary syndrome (ACS). Methods: EDICA assessed 404 patients. Blood samples were obtained on admission, for assessment of high sensitivity-troponin (hs-Tn) and ApoJ-Glyc. ApoJ-Glyc serum levels were analyzed with a novel ELISA, targeting a specific glycosylated variant of ApoJ (ApoJ-GlycA6). Results: Based on clinical diagnostic tests, 291 patients were given a final diagnosis of “non-ischemic” event and 113 patients were considered to have had an ischemic event (33 STEMI, 48 NSTEMI, 27 Unstable Angina and 5 “unclassifiable” ACS). ApoJ-GlycA6 levels were significantly lower on admission in ischemic patients, compared with non-ischemic patients (66 [46-90] vs. 73 [56-95] μg/ml, respectively; P=0.04). Ischemic patients who underwent PCI and had a pre-PCI TIMI 0-2 flow showed significantly lower ApoJ-GlycA6 levels at admission compared with non-ischemic patients (64 [37-81] vs. 73 [56-95] μg/ml; P=0.01). Of interest, 51% of ischemic patients, had “inconclusive” or negative hs-Tn at admission. Among these, ApoJ-GlycA6 identified the ischemic event in 48% (&lt;66 μg/ml). Conclusions: ApoJ-Glyc concentration decreased in patients with documented myocardial ischemia, compared with patients with a final diagnosis of “non-ischaemic” event. Patients with reduced TIMI flow indicative of poorer myocardial perfusion were among those with the lowest ApoJ-Glyc concentration. ApoJ-Glyc was low in ischemic patients irrespective of hs-Tn concentration. The results confirm the potential role of ApoJ-Glyc as a biomarker for the early detection of cardiac ischemia that could provide complementary information to that afforded by current biomarkers and diagnostic tests.
Abstract 14293: Sex Differences in Cytokine and Chemokine Expression in an Experimental AAA Rodent Model
Authors: Mohamed Zaghloul, Santiago Elizondo-Benedetto, Batool Arif, Sergio Sastriques Dunlop, Robert J Gropler, Yongjian Liu, Mohamed Zayed
Journal: Circulation (2022)

Introduction: Abdominal aortic aneurysms (AAAs) are a multifactorial disease process that results from a series of biomolecular processes. AAAs are more prevalent in men; however, women are at greater risk of rupture. Despite continued investigation, the mechanisms of sex disparities in AAA remain unknown. Hypothesis We hypothesize that male and female rats will have different inflammatory cytokine and chemokine expression in AAA tissue. Methods: Male and female Sprague-Dawley rats underwent intraluminal infrarenal abdominal aortic exposure to elastase to induce AAA. Rats were administered daily β-aminopropionitrile to promote AAA rupture. In vivo aortic diameters were evaluated using ultrasound (12MHz) at day 7 and 14 post-AAA induction. PET imaging with 64 Cu-DOTA-ECL1i (a selective radio-marker for C-C chemokine receptor type 2; CCR2), AAA tissue zymography and cytokine array were performed at day 6 and 14 to evaluate CCR2, matrix metalloproteinases (MMP), chemokine, and cytokine content. Results: Male rats developed larger AAAs at day 7 and 14 compared to female rats (p&lt;0.0001; Figure 1A), but AAA rupture rate was similar between sexes. At day 6, AAA cytokine arrays demonstrated Rantes, IFN-y, and IL-17A were higher in males (p&lt;0.01; Figure 1B-D). However, MCP-1, IL-6, IL-10, IL-18, IL-1B, and TNF-α were similar between groups (Figure 1E-J). Interestingly, at day 14, females showed significantly higher MCP-1, IL-6, and IL-10 (p&lt;0.05; Figure 1E-G). PET imaging demonstrated that males had higher CCR2 uptake at day 14 (p&lt;0.05; Figure 1K). AAA zymography demonstrated equivalent levels of total MMP-9, pro-MMP 9, and active MMP-9 between groups (Figure 1L-O). Conclusion Our findings demonstrated that inflammatory cytokines and chemokines are differentially expressed in AAA tissue - particularly CCR2 which is higher in males. This provides sex-specific AAA tissue targets for diagnostic molecular imaging and potential future immune-modulation strategies.
Abstract 12789: Time-Dependent Changes in Mitochondrial Properties and Function in Dogs During Electrically Maintained Atrial Fibrillation
Authors: xiaoyan qi, Jiening Xiao, Feng Xiong, Stanley Nattel
Journal: Circulation (2022)

Introduction: Atrial fibrillation (AF) causes atrial remodeling, leading to progressive resistance to therapy. Changes in cell metabolism likely contribute to remodeling; here, we studied the nature and time course of mitochondrial (MITO) changes during AF . Methods: Atrial cardiomyocytes were isolated from control dogs and dogs kept in AF for 24 hrs, 3 days, 1 and 3 wks by atrial tachypacing at 600 bpm (N=10/group). MITO were visualized with transmission electron microscopy. [Ca 2+ ] Mito (Rhod-2 AM), MITO ROS production (MitoSOX), membrane potential (αψ, JC-1), mPTP opening (TMRM) and FAD autofluorescence were measured via confocal microscope, NADH autofluorescence was determined under UV light. Protein expression was assayed by western blotting. Results: MITO elongation occurred following 24-hr and 3-day AF, while 3-week AF induced MITO fragmentation, rupture and shrinking (A). MITO fusion protein (MFN1) decreased from 3 days to 3 wks of AF and fission protein pDRP1ser-616 was increased at 1 and 3 wks of AF, potentially accounting for MITO fragmentation. [Ca 2+ ] Mito increased progressively with AF-time (B). MITO ROS production increased at 24 hr AF, and remained elevated from 3 days to 3 wks of AF (C). SOD2 was reduced after 3 days AF. NOX4 expression was increased at 3 wks AF. mPTP opening frequency and duration increased progressively during AF (D). AF increased JC-1 fluorescence, indicating depolarized αψ, beginning 24 hours after AF-onset (E). NADH increased by 15% at 24 hr AF, and then decreased progressively with AF-time (F). FAD was decreased during AF. Mitotempo (5-μM) reversed AF-induced atrial-cell I CaL downregulation (G) and reduced triggered activity (H). Conclusions: MITO are activated early during AF, but then show progressive changes likely due to ROS autotoxicity. MITO dysfunction and impaired bioenergetics may contribute to AF maintenance/ progress. MITO-targeted antioxidant intervention may have potential as a novel therapeutic approach for AF.
Abstract 14213: The Polyamine Spermidine Enhances the Contractile Force of μ-Patterned Single-Cell Stem-Cell-Derived Cardiomyocytes Post Doxorubicin Treatment
Authors: Cheavar A Blair, Beth Pruitt
Journal: Circulation (2022)

Doxorubicin (DOX) is a chemotherapy used to treat childhood and adult malignancies, including pediatric leukemia and breast cancer. However, despite being a cornerstone for oncological care, the use of DOX is limited due to dose-dependent cardiotoxicity, which can lead to contractile dysfunction and heart failure. Yet, Dox is still widely used due to the lack of suitable replacements. The exact mechanism of Dox-induced cardiotoxicity is not fully understood. However, proposed mechanisms include sarcomere degradation and impairment of autophagy. To determine whether enhancing autophagy can restore contractile function, we treated μ-patterned single-cell human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), displaying sarcomere disarray and reduced contractile force post-Dox treatment with spermidine, an autophagy activator. The contractile force was quantified using traction force microscopy. There were five conditions (untreated control, Dox, maintenance medium post-Dox, spermidine post-Dox, and spermidine-only). We found that hiPSC-CMs treated with spermidine post-Dox produce 67% of the contractile force generated by control cells (.22 μN vs. .33 μN, not significant) and significantly (.22 μN vs. .11 μN, p &lt; .0001) higher contractile force compared to cells in maintenance medium post-Dox. In the spermidine-only group, our results demonstrate that spermidine significantly (.57 μN vs. .33 μN, p &lt; .0001) increases contractile force compared to control. Spermidine-only treated cells were also bigger (spread area = ~1716 μm 2 vs. ~1353 μm 2 , p &lt; .00001) than the control and had a more robust and organized sarcomere network. Preliminary qPCR results suggest that spermidine upregulates genes that control sarcomere function (e.g., MYH7) and organization (e.g., ANKD1). These data demonstrate that spermidine can enhance contractile force post-Dox treatment and increase cellular size and sarcomere network in hiPSC-CMs. The data further suggests that sarcomere homeostasis is one of the cellular mechanisms spermidine regulates in hiPSC-CMs. This work opens the door for developing therapies that target autophagy and sarcomere proteostasis to treat cardiac dysfunction.